The present invention relates to a method and apparatus for uniformly mixing sample liquids, reagents or other solutions. In particular, the present invention provides a method for rapidly and uniformly mixing a liquid by generating a vortex mixing action using magnetic mixing.
Automated microbiology and clinical chemistry analyzers identify the presence of microorganisms and analytes in body fluids such as urine, blood serum, plasma, cerebrospinal fluid, sputum and the like. Automated microbiology and clinical chemistry analyzers improve productivity and enable the clinical laboratory to meet the workload resulting from high-test volume. Automated systems provide faster and more accurate results as well as valuable information to clinicians with regard to the types of antibiotics or medicines that can effectively treat patients diagnosed with infections or diseases. In a fully automated analyzer, many different processes are required to identify microorganisms or analytes and an effective type of antibiotic or medicine. Throughout these processes, patient sample liquids and samples in combination with various liquid reagents and antibiotics, are frequently required to be mixed to a high degree of uniformity producing a demand for high speed, low cost mixers that occupy a minimal amount of space. In addition to identifying microorganisms, most automated microbiology systems in particular can also determine the types of antibiotics as well as the minimum inhibitory concentration levels of these antibiotics (MIC) that are required to inhibit microbial growth.
Analyzers like those described above perform a variety of analytical processes upon microbiological liquid samples and in most of these, it is critical that a patient""s biological sample, particularly when in a liquid state, be uniformly mixed with analytical reagents or diluent or other liquids or even rehydrated compositions and presented to an analytical module in a uniformly mixed state. In a biochemical analyzer, other liquids like broth may need to be uniformly stirred before being used. Various methods have been implemented to provide a uniform sample solution mixture, including agitation, mixing, ball milling, etc. One popular approach involves using a pipette to alternately aspirate and release a portion of liquid solution within a liquid container. Magnetic mixing, in which a vortex mixing action is introduced into a solution of liquid sample and liquid or non-dissolving reagents, herein called a sample liquid solution, has also been particularly useful in clinical and laboratory devices.
U.S. Pat. No. 5,586,823 describes a magnetic stirrer comprising a bottle unit constituted by a bottle having a base and a stirrer bar of relatively low power magnetization lying on the bottle base within the bottle, and a permanent magnet means of relatively high power located beneath the bottle base in close proximity thereto, and driving means for continuously rotating the external permanent magnet means about an axis substantially normal to the bottle base so that its rotating strong magnetic field entrains the stirrer bar in continuous rotation in a plane parallel to and above the bottle base within the liquid in the container.
U.S. Pat. No. 5,547,280 discloses a two-part housing magnetic stirrer having a lower part contains a drive while the upper part forms the mounting surface for a mixing container that holds a mixing magnet, and the separating surface of the upper and lower parts runs approximately horizontal when in the working position. The upper part is made of glass and the of this upper part, when in its working position, is tightly pressed against an opposing surface of the lower part. The edge can have a widening that engages into a corresponding undercut of the lower part. This provides a magnetic stirrer that is tightly sealed and impervious to aggressive vapors.
U.S. Pat. No. 5,078,969 discloses a stirrer which is placed on a reaction vessel and used for the staining of biological specimens on microscope slides in a jar. The bottom wall of the jar is perforated and made of glass so that the magnetic flux passes through to couple a stirrer rod to a magnetic drive arm. The jar is seated on a platform with the magnetic-stirrer drive mounted and operable below the platform. The magnetic drive has a motor with magnetic drive arm like a permanent magnetic and a variable speed control device to control the angular velocity of the magnetic arm.
U.S. Pat. No. 4,728,500 discloses a stirrer for biochemical reactions comprising a magnetically permeable vessel containing at least one magnetic bead and a magnetic device having a spacer with a number of longitudinally positioned magnetic bars parallel to one another disposed thereon. The bars may be moved in a longitudinal direction so as to produce an oscillating magnetic field causing the beads to undergo an elliptic motion.
U.S. Pat. No. 4,534,656 discloses a magnetic stirrer apparatus in which the stirrer is buoyant, and thereby floats on the surface of a liquid which is to be stirred. The stirrer is caused to be rotated, generally on the vertical axis of the flask, and is enabled to change its elevation, relative to the bottom of the flask, as the level of liquid in the flask is changed. The floating stirrer is restricted by a guide rod to rotational movement, and to vertical movement as the liquid level changes; a magnetic drive is provided to cause rotational movement of the stirrer, to thereby cause mixing action of the entire body of liquid in the flask, due in part to viscous drag. The guide rod is preferably a non-circular driving guide rod which is suspended from the underside of a closure provided for the upper opening of the flask, and a magnetic drive apparatus causes rotation of the driving guide rod, the apparatus comprising a magnet on the driving guide rod within the flask, and a motor-driven magnet carried on the exterior of the closure or cover for the flask.
U.S. Pat. No. 4,162,855 discloses a magnetic rotor having a central hub which has a surface covered with an inherently high lubricity material and on which is mounted a radially extending magnetic impeller. The magnetic rotor is mounted in a central collar portion of a cage which has a number of frame members extending from the collar to prevent the rotating impeller from engaging the walls of the vessel. As the outward members maintain the cage in position within the vessel, the magnetic rotor is allowed to xe2x80x9cfloatxe2x80x9d relative to the cage and rotate freely, with extremely low frictional forces, relative to the vessel to agitate the substance therein.
Accordingly, from a study of the different approaches taken in the prior art to the problems encountered with magnetic mixing of small volume solutions, taken with the challenges of maintaining a high level of sterilization and, at the same time, minimizing the physical size of a magnetic mixer, there is a need for an improved approach to the design of a simplified, space-efficient magnetic vortex mixer. In particular, there is a need for a mixer which enables uniform mixing of liquid solutions contained in tubes held in a sample tube rack without removing the sample tubes from the rack thereby eliminating the need for costly, spacious mechanisms to move the tube to a separate location for mixing. There is a further need for a method for magnetic mixing that Is of such high speed that multiple mixing processes may be achieved without adversely affecting the time required for liquid solution analysis. There is a even further need for a method for magnetic mixing having a mixing member that is easily placed into a liquid solution container. There is an even further need for a method for magnetic mixing having a mixing member that has such a low manufacturing expense that it may be disposed after use without adversely affecting the cost of liquid solution analysis.
Many of these disadvantages to the prior art are overcome by using the apparatus and/or methods of this invention. This invention provides a method for mixing a liquid solution contained in a liquid container by causing a freely disposed, spherical mixing member to rapidly oscillate within the solution in a generally circular pattern within the container. The spherical mixing member is caused to rapidly move within the solution by revolving a magnetic field at high speed in a generally circular pattern in proximity to the liquid container. Magnetic forces acting upon the magnetic mixing member cause it to generate a mixing motion within the liquid solution. In one embodiment, the magnetic field source is caused to rotate by rotating a permanent or semi-permanent magnet at close proximity to the liquid container using a motor shaft having said magnetic field source attached thereto. In an alternate embodiment, multiple liquid solutions are mixed within respective liquid containers supported in a rack and the rack is moved through the revolving magnetic field while the containers remain within the rack. In an exemplary embodiment, the small magnetic mixing member is shaped like a spherical ball and may be automatically dispensed either at time of manufacture of the liquid solution container or loaded on-board the instrument into a liquid solution container easily. Additionally, a spherical mixing member may be produced in large quantities at very low cost so that is may be disposed after a single use in contrast to prior art stirring members that are typically expensive plastic-coated permanent magnets and are therefore repeatedly used. Repeated use of a plastic-coated permanent magnet or other more expensive mixing member introduces the possibility of adverse cross-contamination between stirrings.